Cerebral small vessel disease (SVD) encompasses a spectrum of pathologies that affect the small vessels of the brain. Manifestation of SVD includes heterogeneous lesions in the brain parenchyma detectable by magnetic resonance imaging (MRI). In particular, white matter hyperintensities (WMH) are commonly-identified lesions in the elderly brain and are widely recognized as a significant predictor of stroke, dementia, and mortality. Genetic factors and hypertension are major risk factors of SVD and genome-wide association studies have recently identified novel loci for WMH. Yet, the common variants at these loci explain only a fraction of the genetic contribution to the phenotypic variance. There are several possible sources of the residual genetic variance or missing heritability, including rare sequence variation and epigenetic variation. However, the contribution of these two sources of variation to SVD risk and its associated comorbidities has not been widely explored. We hypothesize that the interplay between genotype, epigenotype, and risk factor exposure underlies SVD etiology and propose an integrated analytic framework to identify such relationships. The proposed project will use the resources of the 4 large population-based, prospective cohorts of the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, the Framingham Heart Study and the Rotterdam Study to (1) conduct whole-exome association analyses of MRI-defined cerebral SVD using already-collected whole exome sequence (WES) data on over 5000 participants with a brain MRI; (2) conduct blood methylome association analyses of MRI-defined cerebral SVD; (3) identify novel blood methylome signatures that mediate the causal relationships between MRI-defined SVD and exposure to high blood pressure; and (4) investigate whether the combined information on genetic and epigenetic variation predicts susceptibility to clinical events, including ischemic stroke and dementia.